2 Free Issues

Follow

Good News and Bad News About Breast Cancer

Women are more alarmed than they need to be about the chances that they will develop breast cancer. But they are also more confident than they should be that the advances medicine has made in treating the disease and prolonging life mean that it can be cured

Few things frighten a woman more than discovering a lump in one of
her breasts. With good reason: breast cancer may transform a woman's
breast into the vehicle of her death. It is twice as likely to be
diagnosed in an American woman today as it was sixty years ago. And the
treatment—surgery, usually followed by radiation and
chemotherapy—is disfiguring, painful, and all too often unsuccessful.

I have been researching and treating this disease for more than
thirty-five years, a period in which the public's awareness of breast
cancer has risen enormously. The disease has brought into being an entire
industry of research organizations, charitable agencies, commercial
ventures, and advocacy groups. Every new statistic is trumpeted in the
media, and every encouraging research finding, no matter how tenuous, is
held up as a potential breakthrough.

One result of this visibility has been a rise in public sympathy for
victims of breast cancer and a concomitant rise in funding for
breast-cancer research. But the growth in awareness has had another, less
desirable result: a flood of often contradictory information that has led
to public confusion. Paradoxically, women are both too anxious about their
chances of developing breast cancer and too hopeful about our current
approaches to diagnosing and treating the disease. They believe that
breast cancer is an epidemic and that it is being cured. Unfortunately,
both these beliefs arise from flawed reasoning—not by women but by
the medical profession.

Two groups in the health-care profession are involved in the fight against
cancer—indeed, against any kind of disease. The first works
principally on the front lines, helping patients understand the therapies
available and offering insight, treatment, and reassurance whenever
possible. The second works mostly at scientific institutions, performing
the methodical, frustratingly slow tasks associated with epidemiology,
clinical trials, and laboratory analysis. As researchers, the members of
the second group are necessarily less concerned with the fate of specific
patients than with understanding specific diseases and whether medicine is
successfully combating them. To move forward, they must coldly distinguish
between genuine advances and wishful thinking. I have spent my career as a
member of the first group, although Ihave also spent years helping to
conduct and analyze clinical trials. In what follows Ihave adopted the
researcher's view of the big picture, while also summarizing the risks and
benefits of the treatments now available to women with breast
cancer—treatments the clinician in me still recommends and performs,
though the researcher wonders how often they will be of meaningful help.
Only by stepping back from the perspective of caring for individual
patients can one hope to make clear what doctors mean (or should mean)when
they use such broad words as "epidemic"and "cure."

IS BREAST CANCER
AN EPIDEMIC?

Many of my patients have conflicting images of their breasts. On
the one hand, breasts are symbols of beauty, sexuality, and nurturing; on
the other, they are troublesome organs that are increasingly likely to
threaten women's lives. In the United States the likelihood that a woman
will be found to have breast cancer has slowly and inexorably mounted
since the 1930s, when some systematic data collection began. The increase
in diagnoses, already a cause for concern, accelerated in the 1980s,
growing by a rate of four percent a year. This year, according to the
American Cancer Society, some 184,300 women will discover that they have
the disease; another 44,300 will die of it. Of the women in whom cancer is
diagnosed, 9,200 will not yet be forty—nearly twice the number of
women under forty who were found to have breast cancer in 1970. The
disease is now the leading cause of death for American women aged forty to
fifty-five, and causes women to lose more years of productive life than
any other disease. Numbers like these are why breast cancer is often
called an epidemic.

To our grandparents, this picture would have seemed amazing. At the turn
of the century cancer of the breast was a relatively unusual disease. What
happened? Why does the incidence of breast cancer seem so much higher
today?

Some of the increase is more apparent than real. Because women today are
less likely to die young in childbirth or of infectious disease, they live
long enough to develop diseases of middle and old age, breast cancer among
them. And the recent jump in the number of breast-cancer victims under
fifty is almost wholly due to the concurrent jump in the number of women
in that age group, caused by the Baby Boom. A third reason for the
increase in diagnoses of breast cancer is the growing use of mammography,
a technique that uses x-rays to examine the breast. With mammography
doctors catch many cancer cases earlier than they otherwise would
have—and some cases that would never have been caught at all. The
technique surged in popularity in the 1980s, and accounts for much of the
recent spurt in diagnoses. (Now that mammography is routine, the rate of
increase in diagnoses has slowed.)

At the same time, most experts in medical statistics believe that these
factors do not explain all of the rise. Even when greater
longevity, the population bulge, and the introduction of mammography are
taken into account, a real, underlying increase remains. Minus those three
factors, the chance that a woman will be found to have breast cancer has
been growing steadily for decades, at roughly one percent a year.

What lies behind this rise? Although there is not enough evidence to say
with certainty, an increasing number of observers have come to believe
that the emergence of breast cancer as a widespread health problem is tied
to the extraordinary transformations in women's lives. Coupled with better
nutrition, the expansion of opportunities for women, especially in the
industrialized West, altered not only women's lives but also their bodies,
and especially their cycles of reproductive hormones—apparently
making them more susceptible to certain cancers.

For most of human history menarche, the age of first menstruation, usually
occurred in the late teens. (This is one reason that previous generations
saw less early-teenage pregnancy—fewer adolescents were
physiologically capable of having babies.) Once fecund, women of past
millennia quickly became pregnant with the first of perhaps half a dozen
children, each of whom they breast-fed for an extended period—a
practice that regularly stops the menstrual cycle. If they survived to
their mid-thirties, they were aged in appearance and probably
post-menopausal; their brutal living conditions usually did not permit
them to live much longer. Late menarche, multiple pregnancies, long
nursing times, early menopause—all these combined to make women of
the past menstruate much less often than their modern counterparts. Many
women in the past may have ovulated only twenty times in their entire
lives.

This grim picture changed only recently. Not until modern times has a
large percentage of humankind been able to obtain a continuous supply of
nutritious food and potable water or been able to control infectious
disease. The average age of menarche has fallen to twelve in Western
industrialized nations. Meanwhile, the age of first marriage has risen.
According to the U.S. Census Bureau, it
now averages twenty-four for women
in this country; many educated and affluent women do not marry until their
thirties, partly because of the increased opportunities to have careers
outside the home. Pregnancy, too, has become much less common, as lost
working time drives up the cost of having babies. Marriages produce an
average of two children, which women nurse briefly if at all. And
menopause does not occur until age fifty or later. Women today are thus
exposed to reproductive hormones over a much longer span than in the past.
They may have 300 to 400 periods—fifteen to twenty times as many as
their ancestors had, exposing their breasts to historically unprecedented
numbers of estrogen-progesterone cycles.

Estrogen and progesterone, like aspirin, have such familiar-sounding names
that people often don't realize how powerful their effects are. Among
these effects is the multiplication of cells within the breast. With
repeated menstrual cycles that are rarely interrupted by full-term
pregnancy, the number of cells in some parts of the breast can increase by
a factor of a hundred or even more. If only because of the simple increase
in number, this constantly repeated cellular multiplication is believed to
increase the likelihood of genetic accidents. Most cancers are believed to
arise from such accidents, and so the strong suspicion is that repeated
menstruation is a precursor to cancer of the breast.

If the improvements in women's lives have indirectly promoted breast
cancer, then it is unhelpful to call the growth in its incidence an
epidemic. In medical terms an epidemic is the sudden outbreak of a
generally rare condition, such as the deadly spread of cholera in a city
with contaminated water, and should be stopped by striking at its
source—in this example the contaminated water. The "epidemic" of
breast cancer, in contrast, may be an unwanted accompaniment to what most
Americans view as social and material progress. If this suspicion is true,
it is obviously unacceptable to eliminate the epidemic's cause.

Equally important, the increase in breast cancer does not resemble other
epidemics. Although the likelihood that a woman will be found to have the
disease has climbed, the likelihood that it will end her life has not.
After adjustments for today's longer life-span and the population bulge
associated with the Baby Boom, the proportion of women who are killed
every year by breast cancer—24.7 to 27.6 per 100,000 —has
remained little changed since the 1930s. Women face an ever-increasing
risk of being discovered to have breast cancer, then—but not of dying
from it. It is highly unusual, to say the least, for a nationwide epidemic
of a fatal disease not to affect the death rate.

This odd and even paradoxical situation has sown much confusion and fear.
Breast cancer is a major public-health concern; it kills 0.04 percent of
all American women yearly. But it is important for women to recognize that
other conditions, especially the various forms of cardiovascular disease
and, for smokers, lung cancer, are much more likely to claim their lives.
Unfortunately, the enormous publicity accorded the rise in breast-cancer
incidence has obscured the fact that the disease is not the leading killer
of women. Also, the publicity usually obscures the fact that the majority
of women who die of the disease are elderly. In a survey conducted by
three researchers at the
Dartmouth Center for the Evaluative Clinical Sciences and published in
May of last year in the Journal of the
National Cancer Institute, the median estimate female Baby Boomers
gave of their chance of dying of breast cancer within a decade was 10
percent. A substantial minority thought the risk was 30 percent or more.
In fact, the likelihood that a woman in her forties will die of breast
cancer in the next ten years of her life is on the order of 0.4 percent.

In my view, the medical profession, too, has lost perspective. If a
woman's chances of dying of breast cancer are little changed despite a
huge rise in the incidence of the disease, there are two possible
explanations. First, we could be making progress. To go on from the
current hypothesis: as women's changing hormonal environment slowly drove
up the number of breast-cancer cases, our mastery of the disease could
have grown at such a rate that, year after year, the increase in cures
precisely canceled out the increase in incidence, leaving the overall
death rate unaffected. When my colleagues claim that we are curing breast
cancer, they are implicitly endorsing this view. And why not? When
physicians treat more cases of a disease while observing the same number
of deaths, that means a smaller percentage of their patients are dying.

The second possible explanation is that the change in women's hormonal
environment is creating a surge in slow-growing, less-aggressive forms of
breast cancer. Because this "new" breast cancer, if it is indeed
responsible for the rise in diagnosed cases, is a much less dangerous
disease than the breast cancer that was found before, in many cases it
would not need treatment beyond excising the primary tumor. The rise in
incidence would not be matched by a rise in breast-cancer mortality,
because women would die first of other causes. The apparent good news
about the decline in the proportion of fatal cases would in fact be
masking the unchanged prevalence of the "old" breast cancer: a persistent
public-health problem that is just as likely to kill women now as it was
sixty years ago. I believe this is just what we are seeing.

BREAST-CANCER
BASICS

Female breasts are one of the most variable parts of the human
anatomy. Evolved from sweat glands, they are designed to provide milk for
infants through a system of ducts and lobules. The ducts are small tubes
that run several inches back from the nipple to the milk-producing
lobules, which stick out from the ducts like clusters of tiny grapes. Both
are enveloped by fat and connective tissue, which are contained within a
sac of skin shaped roughly like a teardrop. The whole assembly changes
dramatically in size, shape, and constitution during the menstrual cycle,
pregnancy, breast-feeding, and menopause. Not only do breasts vary from
woman to woman but each woman's breasts continue to change throughout her
life.

At any given time a third to a half of all Western women have some kind of
breast problem, although most are not particularly concerned about the
symptoms—nor need they be. The symptoms frequently include swelling
and aching before menstrual flow; women may feel their breasts engorge and
grow tender. If their breasts become lumpier, however, this may be owing
to cysts—fluid-filled balloon-like sacs within the breast. Or the
lumps may be solid, nodular clumps of overgrown breast-duct cells, known
generically to doctors as mammary dysplasia or , the most widely used
term, fibrocystic disease. These conditions are benign—a term doctors
use to mean "not cancerous." ("Benign" does not mean "not painful" or "not
harmful." Many benign conditions should be treated.)

If much of the breast is palpably lumpy, as is often the case, the
diagnosis is usually "benign." Matters are less clear when the problem is
in a small area: "dominant mass" is the term used by most doctors for a
swelling that stands out sharply. In such a case a biopsy is almost
routinely recommended. Sometimes the biopsy involves nothing more than
extracting a sample from the breast with a needle, but the surgeon may
also remove the entire lump. Afterward, the tissue is examined in a
laboratory. Most of the time the news is reassuring; two thirds to four
fifths of all biopsies reveal that the abnormality is not malignant.
(Women in their forties are more likely than older women to have negative
biopsies, because mammograms of their naturally lumpier breasts are harder
to interpret.)Yet the specter of breast cancer remains—many of these
"benign" conditions are statistically linked with the disease.

Breast cancer is as diverse as the breast itself, appearing in many
different guises. Some cancers seem to erupt out of ordinary breast tissue
with an awesome virulence, spreading rapidly throughout the body. When
viewed under a microscope, the cells in these cancers almost always bear
no resemblance to ordinary duct or lobule cells—they have lost all
the specialized characteristics that differentiate cells in the breast
from cells in other parts of the body. "Poorly differentiated"
malignancies, as pathologists refer to them, are usually bad news, no
matter what we bring to bear therapeutically.

Fortunately, these poorly differentiated, clinically virulent cancers are
relatively uncommon. Much more often—perhaps in half of all
breast-cancer cases—pathologists see malignancies that still bear
some of the characteristics of normal breast tissue. These "moderately
differentiated" tumors have a wide range of outcomes, though the prognosis
for the patient is generally more favorable. A substantial number of women
with moderately differentiated tumors will survive for years after
treatment—even decades. In most cases these tumors evolve more slowly
than their poorly differentiated cousins, probably taking years to become
detectable. "Well-differentiated" tumors, a less common form, are more
indolent still. Indeed, pathologists sometimes have trouble ascertaining
whether they are truly malignant; women have a good chance of surviving
them.

In recent years doctors have increasingly encountered a fourth, somewhat
different type of breast tumor:
in situ cancer. Twenty years ago in situ tumors made up
no more than one or two percent of all
breast-cancer cases. Today the figure is 10 percent or more, a five- to
ten-fold increase. In situ tumors are usually small—half an
inch or less across—and confined to the ducts and lobules of the
breast. When diagnosed, these tumors usually appear not to have invaded
the connective tissue or spread elsewhere in the body; like
well-differentiated tumors, in situ tumors are not likely to be
fatal.

I must caution that breast-cancer characterization remains an inexact
science. The categories themselves are fuzzy. Well-differentiated and
in situ tumors can occasionally grow fast and develop into serious,
even fatal, disease; some poorly differentiated tumors respond amazingly
well to treatment. The uncertainty is partly due to a lack of absolute
procedures for distinguishing among the three classifications. Often a
tumor is classified as poorly differentiated by one pathologist and
moderately differentiated by another. Neither doctor could be accused of
making a mistake.

More important, the degree of differentiation does not by itself describe
the malevolence of a tumor. It is important to know too if the tumor cells
respond to estrogen and progesterone—that is, whether they retain the
biochemical equipment to link up physically with molecules of these
hormones. (Given the apparent role of hormones in promoting the disease,
their significance in its outcome is unsurprising.) Up to two thirds of
all breast tumors have enough sensitivity to reproductive hormones to be,
in the jargon, estrogen- or progesterone-receptor-positive; such tumors
tend to grow relatively slowly and can be treated by modifying a woman's
hormonal environment, either with drugs or (rarely) by removing the
ovaries. Estrogen- or progesterone-receptor-negative tumors generally have
poorer outcomes.

Even when such complicating factors are considered, though, the tumor's
degree of differentiation is a reasonably accurate approximation of its
virulence. The less resemblance cancer cells bear to the tissue that
spawned them, the worse the prognosis for the patient.

Notwithstanding the myriad forms in which breast cancer presents itself,
researchers believe that at a fundamental level all breast cancers are
similar. In their view, breast cancer, like other cancers, is the result
of accidental changes in the genetic makeup of a cell—mutations. When
the cell reproduces, it passes on its altered DNA. It begins to reproduce
independently, regardless of the body's needs—the defining
characteristic of cancer. Cells depend on nutrients and oxygen from the
bloodstream. Under ordinary circumstances aberrant, independently growing
cells would outpace the available blood supply by the time they had formed
a blob of tissue one or two millimeters in diameter; they would then die
from a lack of oxygen and food. Instead cancer cells—by means that
remain frustratingly unclear—create their own network of blood
vessels to secure necessary nutrients. Once this circulatory system is
established, the nascent tumor can continue to grow at its own pace.
Eventually a discrete mass of aberrant cells becomes identifiable, either
as a denser area on a mammogram or as a lump detectable by touch.

As the cancer progresses, it can invade the surrounding tissue and spread
throughout the body in the familiar and frightening process known as
metastasis. Metastasis is almost always how breast cancer kills its
victims. Left untreated, as it generally was in previous centuries, the
original, or primary, tumor usually grows very large, sometimes to the
size of a grapefruit. Eventually it begins to outstrip its self-generated
blood supply; portions of the tumor die, leading to ulceration of the
breast surface and eventual death from infection, hemorrhage, or both.
Today this peril is avoided with relative ease by removing the tumor. The
metastases are quite another problem. As it grows, the primary tumor sheds
cancer cells into its self-generated network of blood vessels. Spreading
through the body, these cells can lodge in almost any vital organ,
creating a second tumor—or a third, or a fourth. Like the primary
tumor, the new tumors create their own blood supply, each one siphoning
off nutrients from the body to feed its expansion. When the metastases
reach an appreciable aggregate size—a total tumor load of two pounds
or so, scattered throughout the body—the struggle for life is usually
over.

From an intellectual point of view, metastasis is an amazing phenomenon.
If a surgeon inserted a microscopic clump of normal cells from a woman's
breast into another organ, the body's defense systems would wipe out the
misplaced normal cells almost instantly. Yet cancer cells that split off
from the main tumor and lodge elsewhere in the body not only survive but
can grow exuberantly. For this reason most doctors believe that the best
method for stopping breast cancer is to detect it before it has spread.
Find the problem while it is still small and isolated—that is the
hope.

The best method for early clinical detection of breast cancer is
mammography. The American Cancer Society advises women aged forty to
forty-nine to have mammograms every one to two years, and women aged fifty
and over to have them annually. Women with any potential cancer symptoms,
such as suspicious lumpiness of the breast, should see their doctor
immediately.

We have been trying to treat breast cancer aggressively for decades. Many
physicians now believe that the long effort to detect and control this
disease is meeting with success. I shall argue otherwise. Despite the
hopes pinned on mammography, it has had little impact on women's
health—indeed, it may have had none. And although we have taken some
important steps forward in our treatment of breast cancer once it has been
diagnosed—steps that can add years to a woman's life—we are
still far from curing the disease.

DOES
MAMMOGRAPHY HELP?

Finding breast cancer as early as possible seems to be a great
idea, like trying to diagnose high blood pressure before it damages the
heart or the kidneys. And mammograms can occasionally detect tumors as
small as an eighth of an inch across, whereas the lower limit for tumors
diagnosable by palpation (examining the breast manually) is about half an
inch across. Yet one would like to be sure that this difference actually
translates into a higher likelihood that treatment will be successful. An
official nationwide mammography program would be a huge commitment: 51.5
million American women are aged forty or above. And one must bear in mind
the cost of needless medical procedures generated by the huge number of
false-positive mammograms—two to four false positives for every true
positive, according to some measures. (A false positive shows a mass or
lump that proves after further testing not to be cancerous.)We continue to
consider creating a national screening program, but I believe it has never
been proved that such a program would, on balance, be beneficial—even
if it served the secondary purpose of bringing into the health-care system
women who otherwise could not afford it or would not see a doctor
frequently.

To prove the value of mammography scientifically is more difficult than it
might seem. In some studies investigators ask women to volunteer for
screening, and then report the number of breast-cancer cases and the
percentage of women who survive five years after diagnosis. This figure is
compared with the percentage in the population at large. In these studies
researchers often go to considerable trouble to eliminate potential
sources of confusion. For example, they may try to match by age the women
undergoing regular mammography with other women. Or they may match by race
or socioeconomic class. No matter how hard researchers try, though, such
studies remain susceptible to three of the most common sources of bias in
medical research.

Mammography may find a tumor as early as two years before it could have
been detected by palpation. Let us, however, consider a hypothetical case
in which the cancer has already spread to other parts of the body by the
time it is discovered, and the woman goes to her grave on exactly the same
day she would have if the tumor had been discovered later. In that case
the sole effect of early detection has been to stretch out the time in
which the woman bears the knowledge of her condition. But that is not how
the woman would appear statistically if she had happened to become part of
a research study. Pushing back the date of first diagnosis would increase
the interval between diagnosis and death, apparently lengthening her
survival. Statisticians call this effect "lead-time bias." Although
nothing has actually changed, a woman who would have died, say, three
years after treatment now dies five to six years after
treatment—manufacturing an apparent victory for medicine.

A second problem with measuring the benefits of mammography is known as
"length bias." Women typically have mammograms every year or every other
year. Any cancers that are found between mammograms will be detected by
palpation—very possibly by the woman herself. Such tumors are likely
to be fast-growing; indeed, their rapid onset often explains why they were
not picked up by the previous mammogram. The more aggressive tumors tend
not to be diagnosed mammographically, and thus the tumors that are
discovered by mammograms are often less dangerous. Mammography will be
made to look good in a study comparing the survival rate of women whose
tumors were diagnosed by mammography with that of women whose tumors were
diagnosed by palpation, because the tumors discovered by mammography tend
to be those that grow relatively slowly and thus take longer to kill
patients.

The third and most important problem is "selection bias." This occurs when
researchers measure the effect of a treatment on a group of people without
realizing that those people are different from the general population. The
risks that selection bias will occur are high, because women who
participate in medical experiments are often not like the general
population. Researchers typically work in teaching hospitals and thus draw
their subjects from the patients who frequent them. These people may be
more affluent than most Americans, and thus more prone to diseases of
affluence. Or they may be more worried about their health, and thus more
likely to seek expert medical care. In either case, the results of a test
on such a select group can be misleading.

Many researchers agree that lead-time, length, and selection biases may
flaw the optimistic accounts of the efficacy of mammography that have
appeared in the scientific press and the popular media. Nonetheless, they
support the idea of routinely screening women. The principal reason is
that benefits from mammography have been observed in a special kind of
study known as a prospective randomized clinical trial. In such a trial
researchers randomly divide large numbers of volunteers into two groups at
the outset (prospectively): a control group, which receives ordinary
medical care; and a test group, which receives the medication or procedure
under scrutiny. After a given period of time the two groups are compared.
Properly conducted, such trials avoid all three kinds of bias. Even
prospective randomized clinical trials have their pitfalls, though,
because doctors can't control the actions of their patients. Members of
the test group may fail to take their medicine or to show up for their
medical procedures, and members of the control group may seek out a drug
or procedure they are not supposed to have. As hard as researchers may try
to ascertain levels of compliance, misclassification of a certain number
of participants is inevitable. In addition, the medical care provided at
research centers, which often conduct clinical trials, may not be
representative of the care received by most people.

Nonetheless, by ensuring from the beginning that the test group and the
control group are statistically similar and by tracking everyone in both
groups, these trials can produce data that are as solid as medical
research gets. And several big prospective randomized clinical trials have
reported that women who regularly undergo mammography have, roughly
speaking, 25 to 30 percent less chance of dying from breast cancer in the
decade after initial screening than women who are not screened. Most
breast-cancer specialists thus endorse mammography.

In fact the evidence from these trials is weaker than it sounds. In April
of last year an article in Cancer summarized all eight of the major
mammography trials that have been conducted to date. Six of the trials saw
no significant decreases in breast-cancer mortality as a result of
mammography. "Significant," an important term, means that statistical
tests indicate that the effect is probably not due to chance. Also, the
two significant clinical trials were the first ones completed. "Should the
early trials be accepted as the gold standard and the later ones dismissed
as somehow incompetent?" Charles J. Wright, of the University of British
Columbia, and C. Barber Mueller, of McMaster University, asked in The
Lancet last July. "Surely not, in view of the increasing rigour of
trial design over the past 30 years and the vast improvement in quality of
mammography." Indeed, the two earliest trials have serious potential
shortcomings. Explaining these shortcomings involves delving still further
into technical details; some readers may wish to skip the next section of
this article entirely. The gist of my argument is that the benefits of
frequent mammography as opposed to palpation performed during regular
checkups and also by a woman herself are not well established; if they do
exist, they are not as great as many women hope.

STATISTICAL
TROUBLES

The more important historically of the two trials that showed
significant benefits is known as the HIP trial, after the Health Insurance
Plan of Greater New York, the health-maintenance organization from which
the researchers gathered participants. A classic of medical research, the
HIP trial enrolled 60,696 patients from 1963 to 1966 and followed them for
as long as eighteen years. In 1988 two of its principal investigators, Sam
Shapiro and Philip Strax, won the Charles F. Kettering Prize for
outstanding cancer research, both because the trial was one of the
earliest large-scale attempts to test a preventive health measure and
because it showed that periodic mammography reduced breast-cancer
mortality by 30 percent over a ten-year period.

Notwithstanding the accolades awarded to this pioneering effort, it
suffered from methodological weaknesses. In clinical trials, as I have
said, the subjects should be randomly distributed between the test group
(in this case women who received annual mammograms and clinical breast
examinations) and the control group (women who received ordinary medical
care from their own doctors). Experimenters always fear that they may
introduce bias by inadvertently including or excluding the wrong people.
The HIP trial demonstrates why they worry.

In this experiment the researchers assigned women to the test and control
groups alternately in order of enlisting, a process intended to produce
groups of equal size and composition. After assigning a woman to the test
group the researchers made two simple determinations: Was she pregnant?
Had she had breast cancer?If the answer to either of these was yes,
Shapiro and Strax made the woman ineligible for the test group. They did
not, of course, want to x-ray pregnant women. Nor did they think it a good
idea to include women with breast cancer, because administering mammograms
to women who had already been treated for the disease would not be a
proper test of mammography for the purposes of the study. The test group
of 30,131 women thus wound up with 434 fewer subjects than the control
group of 30,565 women.

Shapiro and Strax gave the women in the test group annual mammograms and
breast examinations for as long as five years. They then counted up the
number in each group who died of breast cancer within ten years and
compared the two figures. Because 147 died in the test group and 193 died
in the control group, Shapiro and Strax concluded that mammography was
beneficial. But was it?The researchers themselves attributed the "higher
proportion"of the benefit, at least in the first five years, to clinical
breast examination—that is, palpation. In order to be certain that
the remaining benefit was due to mammography, one would have to confirm
that excluding from the test group the 434 women who either were pregnant
or had had breast cancer did not skew the results.

The ages of the women in the HIP study ranged from forty to sixty-four.
Because few women in this age range are pregnant, most of the subjects
excluded from the test group were surely dropped for having had breast
cancer. In order to guarantee that the test and control groups were
identical, the investigators would also have had to identify and exclude
all the women in the control group who had breast cancer when the
experiment began, by asking the same two questions they had asked women
assigned to the test group. But they did not do this—they simply
filed the names of the women in the control group, without performing any
initial evaluation. (This was not unusual for control groups of the time.)
As the trial progressed, the team leaders later wrote, women in the
control group who "were identified through other sources as having had
breast cancer diagnosed before their entry dates . . . were dropped from
the investigation."In other words, the researchers tracked them by looking
for their names in medical records, insurance claims, and death records;
if they found evidence that breast cancer had been diagnosed in a member
of the control group prior to 1963, when the study began, the scientists
retroactively dropped her from the study. This meant that the researchers
sometimes had to ascertain the time of diagnosis by finding very old
records in scattered hospitals or asking family members about events many
years in the past.

For my own research I have attempted to document medical histories, and
can report that it is no easy task. Records disappear; memories are
faulty; people move. More than half the subjects in the HIP study left
that health-maintenance organization within fifteen years. (In one trial I
myself inadvertently transmitted incorrect data to its statistical
administrators: I reported that a deceased patient was alive, because a
busy doctor's office taking part in the trial was unaware of the death.
When this omission was discovered, I asked the National Cancer Institute
to examine the body of research data Ihad supervised, and I was cleared of
any wrongdoing.) In my experience people typically underestimate the time
that has elapsed since a trip to the hospital. Informed of the real date,
they say, "That long ago? I can't believe that much time has gone by!" In
those instances when Shapiro and Strax relied on the memories of patients
and relatives, they almost certainly retained in the control group some
cancer cases that had actually been diagnosed before the trial
began—inadvertently stacking the deck in favor of mammography.

A few such slips would be enough to throw off the entire experiment.
Indeed, if it turned out that Shapiro and Strax had ascribed a mistakenly
late date of diagnosis to as few as twenty-five women in the control
group, the failure to exclude them, too, would have changed the study's
conclusions. Correcting for it would cause the benefit of mammography to
lose statistical significance—the touchstone of medical research.
Twenty-five errors is in this case not a big number; it is equivalent to
about six percent of the 434 patients excluded from the test group. To be
sure, the trial may have been error-free; although they had not initially
excluded from the control group women who had had breast cancer, Shapiro
and Strax wrote that "confidence is warranted" that by the trial's end
they had identified prior breast-cancer cases equally well in both groups.
Still, the vulnerability of the conclusions to such a small error is
troubling.

No such methodological worries seem to afflict the second of the trials to
show a statistically significant advantage from mammography: the
Kopparberg study, named after the county in southern Sweden where it took
place. Beginning in 1977 the Kopparberg trial offered mammography to a
test group of 38,562 women and ordinary medical care to a control group of
18,478 women. At the same time, the researchers performed a second big
trial in another Swedish county. The test group in Kopparberg experienced
a statistically significant reduction in breast-cancer mortality of 40
percent; the mortality reduction in the test group in the other county was
statistically insignificant.

Strangely, though, as the researchers acknowledged, the mortality from all
causes in the two test groups was "identical" to that in the control
groups. In 1988 the late Petr Skrabanek, of Trinity College, Dublin,
pointed out in the British Medical
Journal, "Not a single life was
'saved' in a trial that included over 130,000 women" in both counties. The
women who underwent mammography may have died less frequently of cancer,
but the gain was offset by deaths from other causes, such as heart attack.
Presumably the "extra" deaths reflect the workings of chance. But it is
awkward to argue that a decrease in cancer deaths in the treatment groups
is meaningful while claiming that an equally great increase in deaths from
other causes is a fluke.

One of the most recent clinical trials discussed in the Cancer
article took place in Canada, where a team of physicians gave annual
mammograms to 44,925 women and ordinary medical care to 44,910 women. The
researchers enrolled women in the trial from 1980 to 1985 and followed
their progress for a minimum of seven years. The subjects were divided by
age into two subgroups: those who were forty to forty-nine when they
entered the trial, and those who were fifty to fifty-nine. In neither
subgroup was there an overall difference in mortality from breast cancer
between the treatment and control groups—mammography had no effect.

Mammography supporters immediately dismissed these negative results as
obvious signs of faulty equipment, poor training, or flawed experimental
technique. Typical was the reaction of Charles R. Smart, then the director
of the Division of Cancer Prevention and Control at the National Cancer
Institute. Without presenting any supporting evidence, Smart dismissed a
preliminary report from the Canadian researchers by writing in the journal
Cancer Prevention, in 1990, "The lack of a decrease in mortality
[in older women] suggests problems in the quality of the mammography in
this trial."

Others took the Canadian trial more seriously. In a series of steps that
sowed confusion in many women, the National Cancer Institute and the
American Cancer Society reviewed all the available evidence about
mammography, especially for younger women. In October of 1993 the NCI
reported that mammography provided no certain benefit to women under fifty
but some benefit to their elders. The American Cancer Society continued to
endorse routine mammography for all women over forty. The dispute sparked
by the inability of the Canadian study to find any benefit from routine
mammography became bitter and personal. Angry critiques poured into the
journals, and the Canadian researchers defended themselves with equal
vigor. Contradictory editorials abounded.

The attacks and counterattacks clearly demonstrated how hard it has been
to prove unequivocally that mammography has a strong beneficial effect on
women's lives. Trying to resolve the controversy, several research teams
employed a technique called meta-analysis. Roughly speaking, meta-analysis
involves adding together the data from many clinical trials to create a
single pool of data big enough to eliminate much of the statistical
uncertainty that plagues individual trials. It is accomplished by
gathering all available studies and comparing them one at a time with the
"null hypothesis"—in this case the hypothesis that mammography has no
impact whatever on mortality from breast cancer. If the null hypothesis is
true, the series of comparisons should randomly differ from zero; added
together, the chance variations will cancel one another out. If the
studies consistently find an impact, the comparisons will draw the total
away from the null hypothesis and toward the actual effect. The great
virtue of meta-analysis is that clear findings can emerge from a group of
studies whose findings are scattered all over the map.

In January of last year a team led by Karla Kerlikowse, of the University
of California at San Francisco, published in the Journal of the
American Medical Association the results of a meta-analysis of the
eight trials: mammography reduces the seven-to-nine-year mortality from
breast cancer in women aged fifty to seventy-four by about 23 percent, but
it has no impact on women in their forties. A second meta-analysis of
mammography for women in their forties appeared three months later in
Cancer (the summary referred to above; its authors included Charles
R. Smart, now retired). Including somewhat more recent data from the same
trials, with an average follow-up time of 10.4 years, the Cancer
article concluded that mammography in fact lowered the rate of mortality
from breast cancer in women aged forty to forty-nine by about 16 percent.
Indeed, these researchers argued, the true benefit was likely to be
greater than that. First, the technology of mammograms is constantly
improving. Second, not all the women in the groups scheduled to receive
mammograms actually showed up for their examinations. Finally, Smart and
his associates presented an argument for eliminating from consideration
the results of the Canadian trial, because it had what they regarded as
worrisome problems. For instance, almost four times as many advanced
cancers were diagnosed in the women who had mammograms as in the women in
the control group—a disproportionately high number of very dangerous
tumors, which in the critics' view makes the experiment unrepresentative.
If data from the Canadian trial were discarded, the researchers
calculated, mammography would lower the rate of mortality from breast
cancer for women in their forties by 24 percent.

Do the meta-analyses settle the matter? Yes and no. Even if one accepts
the highest values from these overviews for the risk reduction associated
with mammography—23 percent for women over fifty, 24 percent for
women in their forties—the figures do not mean what people think when
they read headlines about them. The percentages refer to the relative
risk reduction—a statistical measurement calculated by dividing
the difference between the risks in the test and control groups by the
risk in the test group. For example, if a clinical trial shows that a
treatment cuts the risk of dying from a disease from 70 percent in the
control group to 50 percent in the test group, the relative risk reduction
is 70 minus 50, or 20, divided by 50, which works out to 40 percent. This
percentage sounds large, and it is of great import to medical researchers.
But it has little to do with the question of interest to individual
women—the absolute difference in risk between those who are
screened and those who are not. Using the example I just gave, that
difference would be 20 percent—half the relative risk reduction. In
other words, the figure from the meta-analysis is the answer to the
question "Given that I have breast cancer, how much will I have cut my
risk of dying if the tumor was detected mammographically?" It is not the
answer to the question "If I am a typical woman, how much will I cut my
risk of dying from breast cancer by having an annual mammogram?"

Unfortunately, in this case the absolute reduction is much smaller than
the relative reduction. According to a rough calculation described by
Russell Harris and Linda Leininger, of the University of North Carolina at
Chapel Hill, in the Annals of Internal Medicine in April of last
year, annual mammographic screening for 10,000 women aged fifty to seventy
will extend the lives of only two to six of them each year. ("The many
must be screened to benefit the few," Harris and Leininger remarked.) For
younger women, they argued, the benefit is even more meager: annual
screening of 10,000 women in their forties will extend the lives of just
one or two a year. As Harris and Leininger observed, "the use of the term
'marginal' to describe this risk reduction seems justified."

Even this small benefit may be more apparent than real. Almost all
breast-cancer experts agree that mammography, which can diagnose smaller
tumors, picks up some slow-growing cases of cancer that might otherwise
never be caught. If these tumors grow sufficiently slowly, they will
rarely become dangerous in a patient's lifetime. Discovering them will
thus manufacture an apparent excess of "cures." Because we will detect the
same number of big, dangerous, fast-growing tumors, the "cures" of
slow-growing cancers will appear statistically only a number of years
after diagnosis. Even if mammography had no actual effect on mortality, it
would still produce a small statistical increase in survival many years
down the pike. In a clinical trial the test group, with its frequent
examination by mammography, would have a greater number of less-dangerous
cancers diagnosed within it than would the control group—a form of
length bias that would lead predictably to the modest prophylactic effect
observed in the meta-analyses.

Society should ensure that this effect is worth the cost of obtaining it,
which includes both the direct cost of mammography itself and the indirect
cost of biopsies, laboratory analyses, and the time women must take off
from work for checkups. (The emotional costs of the huge number of false
positives are substantial too, but cannot be reckoned by this kind of
accounting.) Charles Wright and C. Barber Mueller calculated in their
Lancet article what they called a "low" estimate for the cost of
mammography: $1.2 million for each woman benefited. Two previous
cost-benefit analyses, they noted, produced comparable figures.

Now contrast the cost of mammography with that of another widely used
cancer-screening technique: the Pap smear for cervical cancer. Named after
George Papanicolaou, the physician who developed it in the 1930s, the test
is less expensive than mammography, simpler to perform, and far more
reliable. Because the Pap smear can detect cervical cancer in its long
latent stage, before the cancer invades surrounding tissue, the test is
widely believed to reduce the mortality of invasive cervical cancer by 90
percent. According to a study published in 1990 in the Annals of
Internal Medicine by David Eddy, of the Duke University Center for
Health Policy Research and Education, screening 10,000 women with a Pap
smear every three years from their twenties to their seventies would
prevent about 200 of them from developing invasive cervical cancer; if
each detected cervical cancer translated into an additional ten years of
life, the cost to society would be approximately $150,000 per woman
benefited. Eddy's calculation cannot be directly compared with that of
Wright and Mueller, because it used a different methodology. Nonetheless,
it is clear that Pap smears provide much more benefit than mammograms, at
a small fraction of the cost.

Is mammography worth it? I would argue, with Wright and Mueller, that "the
benefits of mass population screening, even in older women, are too small
and the harm and cost generated too great to justify widespread
implementation of screening mammography." In fact, the authors suggest
that routine mammography should be recommended only for women at high risk
of developing breast cancer, such as those whose mothers or sisters
developed breast cancer early in life. There is little factual basis for
this plausible-sounding suggestion, though.

A similar radical stance was adopted by Michael Baum, the research
director of the British Institute of Cancer Research, who quit England's
national breast-cancer-screening advisory board last September because
nationwide mammography is "not worth doing." Having helped to set up the
country's screening program, he was disturbed by claims about the
effectiveness of mammography. The London Sunday Times quoted Baum
as saying, "There is a political correctness about screening. I took pride
in setting up the service, which is as efficient as it can be, but just
because you are doing something efficiently, it doesn't mean it is worth
doing."

Abandoning widespread mammography in the United States is probably not
feasible. After years of effort invested in encouraging mammography, to
reverse course would cause widespread confusion and anger. Alarmed by the
contradictory recommendations of "experts," women would probably keep
having mammograms, just to be safe—and in their shoes I might do the
same. Moreover, many physicians believe that routine mammography
encourages women to come in for regular checkups, and thus may play an
important role in general preventive medicine.

On balance, then, I reluctantly support the status quo. When my patients
come in for their mammograms, I do not try to dissuade them. But I tell
them that the most optimistic interpretation of the available evidence
suggests that routine mammography has only a marginal effect on a woman's
chances of surviving breast cancer—and that it may have no effect at
all.

ARE WE CURING
BREAST CANCER?

Once a tumor has been found, whether by mammography or
palpation, it must be treated. The basis for the contemporary approach
dates back to the 1890s, when William Halsted, a professor of surgery at
Johns Hopkins University, developed radical mastectomy—the technique
for removing a breast, the underlying chest muscles, and the lymph nodes
in the armpit. A giant in medical history, Halsted was held in such
respect that surgeons after him took an uncommonly long time to admit that
his ideas about cancer were off base. He believed that breast cancer oozed
slowly through the lymphatic system of the body the way foul water from a
brackish pond travels through ditches to other parts of the landscape.
(The lymphatic system is the collection of ducts, lymph nodes, and other
organs that drain the tissue fluid called lymph into the bloodstream.) To
Halsted's way of thinking, breast cancer could be cured by carving a wide
swath around the initial tumor and its draining sites, leaving clear
margins of healthy tissue—a scorched-earth approach.

Seventy-five years later a number of North American researchers began
questioning Halsted's ideas. Instead of seeping slowly throughout the body
from its initial site, breast cancer seemed to hop from place to place as
cells sloughed off by the main tumor mass floated through the bloodstream.
If this was true, removing a woman's entire breast would often be
pointless, because most of the tissue surrounding the tumor would be
healthy. After this heretical notion provoked much controversy among
cancer specialists, Bernard Fisher, of the University of Pittsburgh, put
together a series of large clinical trials that were intended to resolve
the dispute. These trials demonstrated that a much less drastic operation
called a lumpectomy was appropriate in many cases; when combined with
radiation therapy it provided a chance of survival indistinguishable from
that provided by Halsted-style mastectomy. After the results were
published, in the mid-1980s, surgical practices changed. Remarkably,
though, they didn't change very fast. Even today only a third of the women
who undergo breast surgery have lumpectomies, whereas at least two thirds
probably could, in light of the size of their tumors. The rest have
modified radical mastectomies, a somewhat less severe version of Halsted's
operation.

In the same period researchers questioned another tacit assumption about
breast cancer: that lumps in the breast appear suddenly and must be
treated quickly. Instead we have come to think that most breast tumors
take years to develop to detectable size; some need decades. In its
initial stages the tumor would be visible under a microscope—if one
could somehow scan the entire breast with such precision. Only after
months or years, however, can the malignancy be detected on a mammogram or
by palpation. Yet standard practice still involves a rush to operate after
diagnosis. The patient wants to know the details of her condition right
away, and surgical exploration is the only conclusive means of providing
this information. But surgeons also operate partly in the name of "getting
this thing out before it spreads." I cannot count the number of times I
have seen a surgeon solemnly tell anxious family members in the hospital
waiting room, "Well, we got it all." Although surgeons today target their
work more carefully and humanely than they did in the past, they still
ignore a crucial fact: we cannot know whether we "got it all." Although
our treatments can eliminate the primary tumor (not a small consideration,
given its potential danger), there is little evidence that we actually
eradicate breast cancer in any more patients than we did decades ago.

As I said, switching when appropriate from mastectomy to lumpectomy leaves
survival rates unaffected—the less-severe operation simply does the
same job. And we have, in my view, less than compelling evidence that
routine mammography benefits otherwise healthy women. Any improvement in
our treatment of breast cancer must therefore come from radiation or
chemotherapy, both of which are by now standard practice. After a
lumpectomy, according to a meta-analysis published last November in the
New England Journal of Medicine, radiation decreases the risk of
recurrence in the breast region (local-regional recurrence, as it is
known) to that associated with full mastectomy—five to 10 percent
during the next ten years. Without radiation the risk is about 20 percent.
But radiation has no known effect on distant metastases from breast cancer
(nonlocal recurrence), which are the chief sources of danger. As a result,
post-surgical radiation has no demonstrable effect on survival—a
point seldom made clear to patients. Reducing local recurrence is a
reasonable goal, because any tumor in the breast could be lethal. But it
will not diminish the danger from metastases.

Nor should we think that the modest benefit from radiation has no price.
Radiation therapy is rough on the body. It kills cells, inducing
inflammation in the breast. Responding to the inflammation, cells called
fibroblasts proliferate and lay down scar tissue. Fifteen to twenty-five
years after radiation therapy tissues in the irradiated area often feel
thick, hard, even wooden—a strange, unpleasant sensation. Meanwhile,
the blast of radiation may have created genetic damage that will lead to
other types of cancer. For instance, worrisome evidence suggests that
radiation may promote lung cancer in the irradiated side of the body. The
risk seems slight, but its mere possibility should remind physicians that
radiation therapy is not without its price.

Chemotherapy is a more complex issue, with better-established benefits and
fewer side effects than it had in the past. Chemotherapeutic compounds
kill cancer cells; the hope is that they will destroy any metastases
lurking in the body. Thirty years ago chemotherapy was a treatment of last
resort, administered only to patients with extensive metastatic disease. I
can recall flying overnight to the University of Wisconsin in 1959 to pick
up some precious vials of 5-fluorouracil, one of the first,
then-experimental chemotherapeutic treatments, for a woman whose cancer
was overwhelming her liver. I was dismayed when the drug made her
extremely sick, though I thought that it might have postponed her death a
little. In the early 1970s researchers discovered that chemotherapy was
also effective when several agents were administered right after
surgery—as an adjuvant treatment, in the jargon. Today chemotherapy
is usually given in the form of a pharmaceutical cocktail, one of the most
common being cyclophosphamide (sold principally under the trade name
Cytoxan), doxorubicin (Adriamycin), and the original 5-fluorouracil (sold
under several names, but usually called 5-FU). Although we have discovered
how to moderate the side effects of chemotherapy, it is still heavy going.
Common complaints include fatigue, nausea, hair loss, mouth sores,
diarrhea, and premature menopause.

Chemotherapy is more effective in younger, pre-menopausal women than in
older, postmenopausal women. Many researchers believe that premenopausal
women receive this extra benefit because the drugs chemically destroy the
function of their ovaries, frequently stopping their monthly
estrogen-progesterone cycles. The decline in hormone production affects
the two out of three tumors that are estrogen- or
progesterone-receptor-positive. Deprived of the chemical catalyst they
need to grow, the metastases often shrink, lengthening the time until they
become dangerous.

Before chemotherapy, doctors sought to create a similar effect by directly
removing patients' ovaries. If the cancer recurred, they tried to amplify
the effect by removing women's adrenal glands. These small, triangular
organs sit atop the kidneys and secrete hormones, one of which is DHEA, a
still-mysterious substance that is a favorite preoccupation of health
faddists. Most women convert some of the DHEA into estrogen, thus
producing small amounts of estrogen after menopause. Even cutting out the
adrenal glands—a procedure involving major abdominal
surgery—wasn't the final step. In their zeal to combat estrogen,
doctors also injected women with testosterone or prescribed synthetic male
hormones.

Although these treatments sometimes slowed the progress of breast cancer,
their cumulative impact was horrific and even barbarous. After having the
breast and underlying tissue on one side of her chest cut away and covered
with a thin skin graft, a woman could be subjected to intense radiation
tharapy, primitive forms of chemotherapy, the removal of her ovaries, and,
eventually, the removal of her adrenal glands. If this failed, she might
be injected with male hormones that made her skin oily, pimply, and hairy.

Things are better today. Surgery is often less severe; chemotherapy can be
more tolerable; and, perhaps most important, there is a substitute for
removing the adrenal glands and injecting women with testosterone. In the
1970s researchers discovered that the actions of estrogen and other
hormones can be blocked chemically by drugs called hormone antagonists, of
which the most noteworthy is tamoxifen, which is sold under the trade name
Nolvadex. Circulating in the body, tamoxifen molecules prevent breast
cells from linking up to estrogen or progesterone molecules by attaching
themselves to the cells in their place, blocking the hormones completely.
Because hormones can stimulate the growth of the majority of breast tumors
that are estrogen- or progesterone-receptor-positive, the potential of
tamoxifen for treating this type of cancer is clear. (Tumors that do not
respond to hormones grow faster and are less treatable.) Tamoxifen can
cause irregular periods or aggravate hot flashes; it also apparently
increases the risk of uterine cancer. But it is a vast improvement over
removing women's adrenal glands.

Many studies have shown that the unwanted side effects of chemotherapy and
antihormonal therapy are offset by the benefits. A compelling example is
the Early Breast Cancer Trialists' Collaborative Group, an Oxford-based
meta-analysis of 133 randomized clinical trials around the world which
examined the effects of chemotherapy and antihormonal tamoxifen therapy on
74,652 women with breast cancer. In the trials breast-cancer patients were
usually given mastectomies or lumpectomies and then divided randomly into
two groups: one that received some type of chemotherapy or antihormonal
therapy (the test group) and one that did not (the control group). The
Oxford group reported in 1992 that women who underwent either treatment
after surgery had a 12 to 14 percent greater chance of surviving for ten
years than those who did not.

Note, though, exactly how this good news was phrased. The improved
survival prospect for women who underwent these treatments was in
comparison with the prospect for breast-cancer patients who received no
systemic therapy—a relative, rather than absolute, increase in
survival. Without chemotherapy, a woman with breast cancer faces a 55
percent chance of dying within ten years, according to the Oxford team.
Chemotherapy cuts the figure to 48.7 percent, an absolute difference of
6.3 percent. Similar figures appeared in the tamoxifen trials. After
surgery 41.2 percent of the women receiving tamoxifen died within ten
years, whereas 47.4 percent of the control group died—an absolute
difference of 6.2 percent. The treatments, then, buy some time for some
women, and this is a very good thing; any woman told that she has even a
small chance of surviving longer with adjuvant treatment will likely
choose it. Nevertheless, we should not be extolling these therapies as
major breakthroughs.

"Wait a minute," some readers may be saying. "Are you being too quick to
dismiss these results? Don't these decreases in risk mean that we are
eliminating this disease in some people? It may be a small number, but
aren't we curing a few more than we did in the past?" These questions are
difficult to answer, not least because they involve coming up with a good
definition of "cure." For instance, if a woman of sixty-five is treated
for breast cancer and then dies five years later of a heart attack, was
she "cured" of cancer? Her family, friends, and even her doctor might
think so, because the disease never troubled her again. Indeed, a common
clinical definition of "cure" is survival for five or ten years. Many
researchers would be less quick to claim a cure, because the cancer might
have been on its way to recurring when the heart attack intervened.

Acknowledging these complexities, statisticians evolved a precise
definition for "cure" in the 1950s. A true cure of a lethal disease like
breast cancer is achieved only when people with that disease face
the same chance of death as others in the population of the same age and
sex. Such true cures are possible with many diseases. Most pneumonia
sufferers, for instance, after recovering with the aid of antibiotics have
exactly the same prospects for survival as people who have never had
pneumonia. Like pneumonia, some cancers, including cervical cancer,
childhood leukemia, superficial melanomas, and Hodgkin's disease, can be
truly cured.

Breast cancer, unfortunately, is not among this select group. As far as we
know, a woman found to have invasive breast cancer is always at higher
risk of dying prematurely than women without breast cancer. Even thirty
years after her diagnosis she is up to sixteen times as likely to die of
the disease as a woman in the general population. That is why responsible
researchers in this field avoid the word "cure." Even as they report
advances, they must acknowledge the reality: Postsurgical chemotherapy and
antihormonal therapy do buy time—an important advance. The slowed
progress of the disease can give a woman additional years of life and even
allow her to die of other, less traumatic, causes. But breast cancer is
every bit as incurable as it was in Halsted's day.

ANOTHER VIEW OF BREAST CANCER

In 1935, 26.2 out of every 100,000 women died of breast cancer.
That was a long time ago, of course, when life expectancy for women was
sixty-four years. Americans now live longer, which means that diseases of
the elderly are more common. Although breast cancer affects many young
women, it is still principally a disease of middle and old age—the
median age at diagnosis is sixty-four. Statisticians must adjust raw data
about incidence and mortality to compensate for underlying demographic
shifts. In 1992, the latest year for which figures are available, the
adjusted rate of mortality was 26.2 women per 100,000—the same as in
1935. (The death rate rose a bit from 1986 to 1989 and declined by about
the same amount from 1989 to 1992.) Since 1935 medicine has seen
improvements in surgical technique and anesthesia, and the introduction of
mammography, radiation therapy, and chemotherapy, along with an enormous
jump in general medical knowledge. But all this progress has had no effect
on the chances that an individual woman will die of breast cancer. To my
way of thinking, the constancy of the death rate in the face of rising
incidence and aggressive treatment is a strong hint that we need to
approach the disease in another way.

When I discussed the evidence relating to mammography, radiation, and
chemotherapy, I was in the realm of fact—although some colleagues may
disagree with my interpretation. In what follows I am moving into
unsteadier terrain. Of course, I believe that my view of breast cancer is
correct, and much of it is shared by other specialists. But I will be
satisfied if I can persuade readers that the mere existence of a coherent
alternative explanation raises questions about the mainstream view.

As I have said, almost all cancer researchers think that the disease is
triggered by an accidental change in the DNA of at least one cell. That
cell divides, producing two cells, then four, then eight, and so on, with
the volume of the tumor doubling in each successive generation. By the
time the tumor has doubled twenty-three times, the original cancer cell
has multiplied to more than eight million. At that point the tumor is
about an eighth of an inch in diameter, just big enough to be detected
(sometimes) by a mammogram.

Such a tumor is not very dangerous by itself; the danger lies in the
metastases. The question is how soon the tumor metastasizes.

For almost thirty years John S. Spratt, a cancer surgeon now at the
University of Louisville Department of Surgery, has been measuring the
growth rates of breast tumors. In one of his most recent studies,
performed in collaboration with researchers from Heidelberg, Germany,
Spratt examined the progressive mammograms of 448 women who had tumors
that turned out to have been visible in mammograms made before the tumors
were diagnosed. (The women's doctors were not necessarily at fault for
missing the tumors; in many cases mammographic imagery is ambiguous.)
Comparing first, second, and even third mammograms provided evidence of
how fast the tumors grew in the intervals. The median doubling time was
260 days, but the range was considerable: the fastest tumor doubled in ten
days, the slowest in 7,051 days—that is, almost twenty years. These
figures have striking implications.

Consider a woman who is unlucky enough to develop a single cancerous cell
on her forty-third birthday. If the woman is especially unlucky, the cell
has a fast doubling time of, say, thirty days. Twenty-three cell
generations later the tumor might be visible on a mammogram; in another
six or seven doublings it will be just big enough to feel. By then the
woman will be forty-five. She will probably die before her fiftieth
birthday. If, though, the woman develops a cancer with a slow doubling
time of, say, 360 days, twenty-three doublings will take about
twenty-three years, at which point the tumor might be seen with
mammography. The tumor will be palpable in another six or seven years,
meaning that without mammography it probably would not be detected until
the woman was in her mid-seventies. By that age some people have already
died of other causes.

I have simplified these calculations considerably. Spratt and his German
colleagues found that breast cancers do not grow at a constant rate but
instead slow down as time passes. Yet the principle holds that tumors that
begin with fast doubling rates grow faster than tumors that begin with
slow doubling rates at comparable stages of formation.

Close scrutiny of tumor doubling times could explain why the earlier
diagnoses provided by mammography seem to provide so little prolonging of
individual lives, despite the statistical appearance of benefit caused by
earlier diagnosis. Although mammography is able to spot tumors as small as
an eighth of an inch, which contain eight million cells, the average size
at diagnosis with mammography is about 600 million cells. Such a tumor is
only a bit more than a quarter of an inch across, but it has already
doubled almost twenty-seven times and may have been in the body for
decades. The average size of tumors detected by palpation is about 45
billion cells and about an inch and a quarter in diameter; these tumors
have doubled an additional eight or nine times. To argue that earlier
diagnosis provides an important benefit, one must believe that the tumor
is considerably likelier to spread in those eight or nine later doublings
than it was in the preceding twenty-seven.

There is no evidence that this is the case; indeed, the small amount of
available data suggests that this view is wrong. With mammography we can
see breast tumors earlier than we could before. But it is illogical to
assume that our newfound ability to observe breast tumors between the
twenty-seventh and thirty-fifth doublings means that they are especially
likely to spread during this time or afterward and not before. If tumors
are more likely to metastasize after rather than before mammography can
detect them, the burden is on mammography advocates to demonstrate it.
Meanwhile, I believe that the reasonable course is to assume that breast
cancer can spread at any time in its development, and that metastasis has
probably already occurred by the time we are able to detect the primary
tumor. If this view is correct—and I should stress that studies to
prove it have not yet been conducted—then it would explain why
research has had such difficulty proving that mammography can save women's
lives.

Similarly, examination of tumor doubling times could explain why
chemotherapy boosts five- and ten-year survival rates but has little
impact on the annual percentage of women who die of breast
cancer—that is, why it helps women with the disease to live longer
but leaves them just as likely to die of metastatic breast cancer in the
end. My best guess is that adjuvant chemotherapy wipes out 95 to 99.9
percent of the residual cancer cells in a patient's body. (It doesn't get
them all because the remaining tumor cells are innately resistant to
chemotherapy.) Expressed as a percentage, the figures are impressive, but
the actual impact is surprisingly slight. Suppose that a woman's tumor has
metastasized and that the new tumor has grown to a million cells—a
lot of cells, but not enough to be seen by the naked eye, or palpated, or
spotted by any current imaging method (CAT scan, ultrasound, magnetic
resonance imaging, and so on). If chemotherapy kills 99 percent of the
cancer cells in a woman's body, this prophylactic treatment will reduce
the metastasis from a million cells to 10,000. The remaining cells, which
are resistant to chemotherapy, will keep on proliferating, more than
likely at the same rate. In six and two thirds cell generations the tumor
will have grown back to a million cells and the woman will be right back
where she was before treatment began.

Cruelly, chemotherapy helps least those who need it most. If a woman's
cancer has the short doubling time of thirty days, the six and two thirds
doublings the tumor needs to recover from chemotherapy translate into
about 200 days. Because chemotherapy is often administered monthly for six
months, the gain is roughly equivalent to the length of treatment.
Producing so much suffering, chemotherapy would in this case be a dubious
exercise. If the woman's cancer has a doubling time of 360 days, however,
she would gain 2,400 days, which is six and a half years. That sounds like
a good payoff, but does she need it?If cancer were diagnosed in that woman
at sixty-four (the median age of diagnosis), her slow-growing metastases
would probably not become life-threatening for twenty to twenty-five
years, when she would be in her late eighties. Because most people do not
live that long, there would be little point in subjecting her to a round
of chemotherapeutic treatment that would give her another seven years when
she probably would die of something else in the meantime. If chemotherapy
has little impact on a woman's chance of surviving either aggressive or
indolent tumors, is it any wonder that it makes few inroads on mortality?

At the same time, chemotherapy should not be dismissed. The calculations
above, for doubling times of thirty and 360 days, represent extremes; I
used them to illustrate my point. A more representative example would
apply Spratt's median doubling time of 260 days to my hypothetical
forty-three-year-old woman. If, as before, the first cancer cell develops
on her birthday, the resultant tumor could take eighteen to twenty years
to show up on a mammogram. (Such calculations are necessarily inexact,
because individual tumors do not always grow at the same rate.) The woman
would then be in her early sixties—near the median age of diagnosis.
With no treatment other than lumpectomy, she would be likely to die before
the age of seventy-five. But if chemotherapy gave the woman the time it
would take the tumor to double another six or seven times, the onset of
life-threatening metastatic disease would be postponed until the woman was
at least eighty; antihormonal therapy might buy an equivalent number of
years. In real terms the achievement would probably be smaller, because
people in their eighties are likely to die of heart disease or some other
condition. Nonetheless, the woman would have gained five to ten years of
life. This is a precious gift, one that she and her doctor can justly
celebrate.

But consider the breast-cancer patients doctors most dread
seeing—women in their thirties or forties. Such cases are relatively
uncommon; breast cancer owes its status as the leading killer of women in
this age group mostly to the even lower likelihood that they will be
killed by anything else. Nonetheless, the individual tragedy of a disease
that strikes down young, vibrant people makes it disproportionately urgent
to treat them. Sadly, younger women in whom cancer is diagnosed are more
likely than older women to have fast-growing tumors, because slow-growing
tumors are usually still too small to detect. Given the probable doubling
rates, these women will be lucky if we can give them an extra five years.
Five years is, of course, much better than nothing—but much less than
the thirty or forty years these women will lose. Anyone who treats younger
breast-cancer patients knows that we will not have made major progress in
the treatment of this disease until we can give women like these, with
fast-growing cancers, thirty doubling times rather than six or
seven.

CANCER OLD AND NEW

In effect, mammography today provides our definition of breast
cancer. Any tumor spotted on a mammogram is treated, almost reflexively,
with surgery, radiation, and often chemotherapy and antihormonal drugs.
Thinking about doubling times suggests the inadequacy of this approach.
When doctors diagnosed breast cancer by palpation in annual exams, they
found principally fast-growing tumors—ones whose average doubling
time, according to the work of Spratt and other researchers, was about
ninety days. Despite decades of work, medicine still is unable to treat
this kind of cancer effectively. Today the spectrum of breast cancer is
different. Perhaps because of the hormonal changes created by the changes
in women's lives, physicians are increasingly likely to observe the "new"
cancer described above, which is slower-growing and much less dangerous.
These cancers, because they progress so much more slowly, have a radically
different impact on women's lives. For that reason we should be more
discriminating in how we treat them.

"New" may be a misnomer for this slow-growing breast cancer. Although its
incidence has risen, I suspect that it has been with us for at least fifty
years; we just weren't able to see it. In fact, I would not be surprised
if someday we are all found to harbor somewhere in our bodies several
small, slow-growing tumors that will never cause us any problems. (They
are beaten to the punch by cardiovascular disease or faster-growing
cancers.)

Among the most important varieties of the new breast cancer is the in
situ tumor—the small, localized, almost nongrowing tumor that at
the time of diagnosis has seemingly neither become invasive nor developed
the capacity to metastasize. Prior to mammography, as noted earlier, in
situ tumors accounted for only one to two percent of all breast-cancer
diagnoses, whereas today in communities where people see doctors often and
have lots of tests, in situ tumors account for at least 10 percent
of all breast-cancer diagnoses. After lumpectomy and radiation, only one
out of ten in situ malignancies recurs in the next five to eight
years.

Most of my colleagues celebrate this as a triumph, because it appears that
we are catching cancers earlier than ever and curing more of them. They
may be right. But consider this—if one out of ten in situ
cancers recurs after treatment, nine out of ten do not. If my view is
correct, even without treatment many or most in situ cancers would
never have grown big enough to be detected by palpation, let alone to pose
a threat to life. They might even have become invasive and metastasized,
but the metastases would also be too small to be detectable and would
never be lethal—rendering the recurrence rate and thus the question
of treatment ultimately unimportant to survival. As a result, mammography
is only leading physicians to diagnose an ever-larger number of harmless
tumors. Patients who otherwise would never have known they have cancer may
needlessly suffer through the unique pain, anxiety, disfigurement, and
expense associated with modern medicine and cancer. For all we know, the
chief effect of mammography has been to disguise our inability to cure the
old cancer, by burying it in cases of new cancer.

WHEN THE DIAGNOSIS
IS POSITIVE

Because of the prevalence of in situ and other
slow-growing breast cancers, women who receive a positive mammogram should
not despair. Two thirds to four fifths of positive mammograms lead to
biopsies that do not reveal cancer. Even if the biopsy indicates cancer,
the patient should keep in mind that not all tumors are truly dangerous,
and she should strive to learn what kind of tumor she has.

Although scientists are divided in their opinion of its accuracy, I
believe that one of the most promising gauges of risk is the "S-phase
fraction," which is a rough measure of a tumor's doubling time, derived
from a technique known as flow cytometry. Technicians calculate this
measure by chopping up a small amount of tumor tissue in a kind of
specialized blender, staining the cell nuclei with a dye, and squirting
the result one cell at a time through a very fine nozzle. The cells shoot
through a thin laser beam, each nucleus casting a shadow as it crosses the
light. Computers record the shadows with enough detail to discern the
approximate percentage of cells in the sample that are dividing. From
these data physicians can infer whether the cancer is aggressive (a
doubling time kf sixty days or less), moderate (sixty-one to 150 days),
indolent (151 to 300 days), or very indolent (more than 300 days). Because
tumor growth rates may change over time, and metastases do not necessarily
march in lockstep with the tumors that spawned them, the actual situation
faced by patients is more complex than indicated by this summary.
Nevertheless, Ibelieve that the broad principle holds:armed with
information about a tumor's growth rate and the patient's age at
diagnosis, doctors could often be more informative than they are now about
what lies ahead for their patients.

If doctors could accurately gauge tumor growth rates, using any
agreed-upon test, my strong hunch is that about a third of the tumors now
detected would be found not to need treatment beyond removal of the tumor
itself. Perhaps another quarter of women in whom breast cancer is
diagnosed could gain considerable time—enough to take them safely
into old age—with antihormonal therapy alone. The remainder could be
helped by the combination of surgery, radiation, and chemotherapy, though
not nearly as much as the providers of these treatments or their patients
would hope. For this last group of women, I am very sorry to say, modern
medicine has less to offer than newspaper headlines suggest. The outcome
was dictated well before diagnosis—by the date the first cancer cells
developed and by the rate at which they grew.

If, as I suspect, a woman's fate is set very early in the development of a
tumor, it seems implausible that advances in detection will have an impact
on the disease. One can always hope that science will develop a wonder
drug that eradicates tumors completely, even when they can't be seen or
felt. But for the present I think we should focus research on improving
our ability to distinguish between women with breast cancer who can
benefit from aggressive treatment and the larger number who will gain
little from it no matter what we do.

The ultimate hope is preventing this awful disease, perhaps by modifying
the contemporary hormonal environment that seems to promote it.
Researchers at the University of Southern California have been examining
ways to lower young women's exposure to reproductive hormones. Another
approach is to use an anti-estrogen drug like tamoxifen preventively in
postmenopausal women whose histories of breast problems indicate that they
are at high risk of developing cancer; I am involved in a study that is
examining this kind of treatment. The risks in changing the hormonal
balance of millions of women are considerable, however, and it seems
likely that any new preventive for breast cancer will have its own side
effects.

Advances in this area will surely be slow, but they may be the only
realistic hope for eventually lowering the death rate from breast cancer.
Meanwhile, we should carefully consider whether we are misleading some
women with messages of unwarranted hope at the same time that we are
needlessly terrifying and hurting other women by diagnosing and treating a
condition that will never pose a threat to their lives.

Most Popular

His paranoid style paved the road for Trumpism. Now he fears what’s been unleashed.

Glenn Beck looks like the dad in a Disney movie. He’s earnest, geeky, pink, and slightly bulbous. His idea of salty language is bullcrap.

The atmosphere at Beck’s Mercury Studios, outside Dallas, is similarly soothing, provided you ignore the references to genocide and civilizational collapse. In October, when most commentators considered a Donald Trump presidency a remote possibility, I followed audience members onto the set of The Glenn Beck Program, which airs on Beck’s website, theblaze.com. On the way, we passed through a life-size replica of the Oval Office as it might look if inhabited by a President Beck, complete with a portrait of Ronald Reagan and a large Norman Rockwell print of a Boy Scout.

Should you drink more coffee? Should you take melatonin? Can you train yourself to need less sleep? A physician’s guide to sleep in a stressful age.

During residency, Iworked hospital shifts that could last 36 hours, without sleep, often without breaks of more than a few minutes. Even writing this now, it sounds to me like I’m bragging or laying claim to some fortitude of character. I can’t think of another type of self-injury that might be similarly lauded, except maybe binge drinking. Technically the shifts were 30 hours, the mandatory limit imposed by the Accreditation Council for Graduate Medical Education, but we stayed longer because people kept getting sick. Being a doctor is supposed to be about putting other people’s needs before your own. Our job was to power through.

The shifts usually felt shorter than they were, because they were so hectic. There was always a new patient in the emergency room who needed to be admitted, or a staff member on the eighth floor (which was full of late-stage terminally ill people) who needed me to fill out a death certificate. Sleep deprivation manifested as bouts of anger and despair mixed in with some euphoria, along with other sensations I’ve not had before or since. I remember once sitting with the family of a patient in critical condition, discussing an advance directive—the terms defining what the patient would want done were his heart to stop, which seemed likely to happen at any minute. Would he want to have chest compressions, electrical shocks, a breathing tube? In the middle of this, I had to look straight down at the chart in my lap, because I was laughing. This was the least funny scenario possible. I was experiencing a physical reaction unrelated to anything I knew to be happening in my mind. There is a type of seizure, called a gelastic seizure, during which the seizing person appears to be laughing—but I don’t think that was it. I think it was plain old delirium. It was mortifying, though no one seemed to notice.

Why did Trump’s choice for national-security advisor perform so well in the war on terror, only to find himself forced out of the Defense Intelligence Agency?

How does a man like retired Lieutenant General Mike Flynn—who spent his life sifting through information and parsing reports, separating rumor and innuendo from actionable intelligence—come to promote conspiracy theories on social media?

Perhaps it’s less Flynn who’s changed than that the circumstances in which he finds himself—thriving in some roles, and flailing in others.

In diagnostic testing, there’s a basic distinction between sensitivity, or the ability to identify positive results, and specificity, the ability to exclude negative ones. A test with high specificity may avoid generating false positives, but at the price of missing many diagnoses. One with high sensitivity may catch those tricky diagnoses, but also generate false positives along the way. Some people seem to sift through information with high sensitivity, but low specificity—spotting connections that others can’t, and perhaps some that aren’t even there.

“Well, you’re just special. You’re American,” remarked my colleague, smirking from across the coffee table. My other Finnish coworkers, from the school in Helsinki where I teach, nodded in agreement. They had just finished critiquing one of my habits, and they could see that I was on the defensive.

I threw my hands up and snapped, “You’re accusing me of being too friendly? Is that really such a bad thing?”

“Well, when I greet a colleague, I keep track,” she retorted, “so I don’t greet them again during the day!” Another chimed in, “That’s the same for me, too!”

Unbelievable, I thought. According to them, I’m too generous with my hellos.

When I told them I would do my best to greet them just once every day, they told me not to change my ways. They said they understood me. But the thing is, now that I’ve viewed myself from their perspective, I’m not sure I want to remain the same. Change isn’t a bad thing. And since moving to Finland two years ago, I’ve kicked a few bad American habits.

Why the ingrained expectation that women should desire to become parents is unhealthy

In 2008, Nebraska decriminalized child abandonment. The move was part of a "safe haven" law designed to address increased rates of infanticide in the state. Like other safe-haven laws, parents in Nebraska who felt unprepared to care for their babies could drop them off in a designated location without fear of arrest and prosecution. But legislators made a major logistical error: They failed to implement an age limitation for dropped-off children.

Within just weeks of the law passing, parents started dropping off their kids. But here's the rub: None of them were infants. A couple of months in, 36 children had been left in state hospitals and police stations. Twenty-two of the children were over 13 years old. A 51-year-old grandmother dropped off a 12-year-old boy. One father dropped off his entire family -- nine children from ages one to 17. Others drove from neighboring states to drop off their children once they heard that they could abandon them without repercussion.

Democrats who have struggled for years to sell the public on the Affordable Care Act are now confronting a far more urgent task: mobilizing a political coalition to save it.

Even as the party reels from last month’s election defeat, members of Congress, operatives, and liberal allies have turned to plotting a campaign against repealing the law that, they hope, will rival the Tea Party uprising of 2009 that nearly scuttled its passage in the first place. A group of progressive advocacy groups will announce on Friday a coordinated effort to protect the beneficiaries of the Affordable Care Act and stop Republicans from repealing the law without first identifying a plan to replace it.

They don’t have much time to fight back. Republicans on Capitol Hill plan to set repeal of Obamacare in motion as soon as the new Congress opens in January, and both the House and Senate could vote to wind down the law immediately after President-elect Donald Trump takes the oath of office on the 20th.

Trinidad has the highest rate of Islamic State recruitment in the Western hemisphere. How did this happen?

This summer, the so-called Islamic State published issue 15 of its online magazine Dabiq. In what has become a standard feature, it ran an interview with an ISIS foreign fighter. “When I was around twenty years old I would come to accept the religion of truth, Islam,” said Abu Sa’d at-Trinidadi, recalling how he had turned away from the Christian faith he was born into.

At-Trinidadi, as his nom de guerre suggests, is from the Caribbean island of Trinidad and Tobago (T&T), a country more readily associated with calypso and carnival than the “caliphate.” Asked if he had a message for “the Muslims of Trinidad,” he condemned his co-religionists at home for remaining in “a place where you have no honor and are forced to live in humiliation, subjugated by the disbelievers.” More chillingly, he urged Muslims in T&T to wage jihad against their fellow citizens: “Terrify the disbelievers in their own homes and make their streets run with their blood.”

A professor of cognitive science argues that the world is nothing like the one we experience through our senses.

As we go about our daily lives, we tend to assume that our perceptions—sights, sounds, textures, tastes—are an accurate portrayal of the real world. Sure, when we stop and think about it—or when we find ourselves fooled by a perceptual illusion—we realize with a jolt that what we perceive is never the world directly, but rather our brain’s best guess at what that world is like, a kind of internal simulation of an external reality. Still, we bank on the fact that our simulation is a reasonably decent one. If it wasn’t, wouldn’t evolution have weeded us out by now? The true reality might be forever beyond our reach, but surely our senses give us at least an inkling of what it’s really like.

The same part of the brain that allows us to step into the shoes of others also helps us restrain ourselves.

You’ve likely seen the video before: a stream of kids, confronted with a single, alluring marshmallow. If they can resist eating it for 15 minutes, they’ll get two. Some do. Others cave almost immediately.

This “Marshmallow Test,” first conducted in the 1960s, perfectly illustrates the ongoing war between impulsivity and self-control. The kids have to tamp down their immediate desires and focus on long-term goals—an ability that correlates with their later health, wealth, and academic success, and that is supposedly controlled by the front part of the brain. But a new study by Alexander Soutschek at the University of Zurich suggests that self-control is also influenced by another brain region—and one that casts this ability in a different light.

A new survey suggests many might prefer a kind of multipolar Washington, with three distinct orbits of power checking each other.

Does Donald Trump have a mandate?

Though last month’s election provided Trump and his fellow Republicans unified control of the White House, House of Representatives, and Senate for the first time since 2006, the latest Allstate/Atlantic Media Heartland Monitor Poll shows the country remains closely split on many of the key policy challenges facing the incoming administration—and sharply divided on whether they trust the next president to take the lead in responding to them.

In addition, on several important choices facing the new administration and Congress, the survey found that respondents who voted for Trump supported a position that was rejected by the majority of adults overall. That contrast may simultaneously encourage Trump to press forward on an agenda that energizes his coalition, while emboldening congressional Democrats to resist him.